ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.722T>C (p.Met241Thr)

dbSNP: rs1555438255
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498748 SCV000589565 likely pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing The M241T variant in the CLN6 gene has been reported previously, along with another variant, in a family with variant late infantile neuronal ceroid lipofuscinoses (Sharp et al., 2003). Functional studies of the M241T variant showed rapid proteasome-mediated degradation compared to wild type cells (Ng et al., 2010; Oresic et al., 2009). The M241T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M241T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. We interpret M241T as a likely pathogenic variant,
Labcorp Genetics (formerly Invitae), Labcorp RCV001203261 SCV001374417 likely pathogenic Neuronal ceroid lipofuscinosis 2019-06-05 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Met241 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 30561534), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant disrupts the stability of the protein leading to rapid degradation (PMID: 18811591, 20430023). This variant has been observed in individuals affected with CLN6-related disease (PMID: 12815591, Invitae and External communication). ClinVar contains an entry for this variant (Variation ID: 431958). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 241 of the CLN6 protein (p.Met241Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine.

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